Rocuronium preparation

Abstract

To provide a new rocuronium preparation that is stable and safe.SOLUTION: Provided is a buffer-free rocuronium preparation comprising rocuronium and having a pH of 4 or less.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to rocuronium preparations and the like.

Background Art

[0002] Rocuronium (rocuronium bromide) is known as an active ingredient in anesthetic muscle relaxants and the like (Non-Patent Document 1).

[0003] Such rocuronium is relatively unstable to heat in an aqueous solution, and its storage and transportation are troublesome and costly. For example, Esrac, known as a commercial product of a rocuronium preparation, is a preparation containing an acetate buffer solution and requires refrigerated storage at 2 to 8°C to ensure stability (Non-Patent Document 1).

[0004] Therefore, attempts have been made to improve the stability of rocuronium in preparations. For example, WO2008 / 065142 (Patent Document 1) discloses a technique for stabilizing an aqueous solution by adding a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof to an aqueous solution containing rocuronium and a buffer (for example, citrate-phosphate buffer).

[0005] However, in the technique of this document, a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof, for which renal impairment and the like have been reported due to use, is required.

[0006] On the other hand, attempts have also been made to stabilize rocuronium preparations without using such components.

[0007] For example, Patent Document 2 (Japanese Patent No. 5684954) discloses a rocuronium preparation in the form of a liquid agent containing rocuronium and a buffer solution and having a pH of 3.5 or less.

[0008] In addition, Patent Document 3 (CN103462885) discloses a stabilized injection containing rocuronium, a stabilizer (buffer), an osmotic pressure regulator, a pH regulator, and water for injection.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0010]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a novel rocuronium preparation.

[0012] Another object of the present invention is to provide a stable rocuronium preparation.

[0013] Still another object of the present invention is to provide a safe rocuronium preparation.

Means for Solving the Problems

[0014] According to the rocuronium preparations of Patent Documents 2 and 3, as described above, the preparation can be stabilized without using the specific components (sulfalkyl ether-β-cyclodextrin derivatives or pharmaceutically acceptable salts thereof) used in Patent Document 1.

[0015] Such stabilization is considered to be achievable or attainable in the presence of a specific pH, specific components, particularly a buffer used as a substantially essential component.

[0016] In particular, according to Patent Document 2, it can be seen that the pH has a great influence on the stability of rocuronium in the formulation. The stabilization of the pH (suppression of the fluctuation of the pH value) in the rocuronium formulation, and thus the use of a buffer, is considered to be essential for ensuring the stability of rocuronium.

[0017] In addition, although there is a reason to consider that a buffer is particularly necessary in the rocuronium formulation, generally, a buffer is a component used for the stabilization of the formulation and the like. Usually, in the formulation, it is not considered to formulate without a buffer. That is, considering comprehensively the influence on the formulation such as stability, usually, a buffer (stabilizer) is substantially an essential component in the formulation.

[0018] In the presence of such common general knowledge in the art, as a result of examining the stability of the rocuronium formulation from a completely different perspective, the present inventors have found, extremely surprisingly, that the stability of rocuronium in the formulation can be ensured without using a buffer, and in particular, that the stability is comparable to or even better than that in the case of using a buffer, and thus completed the present invention.

[0019] That is, the present invention relates to the following inventions and the like. [1] A rocuronium formulation containing rocuronium, having a pH of 4 or less, and not containing a buffer. [2] The formulation according to [1], having a pH of 3.5 or less. [3] The formulation according to [1] or [2], containing an acid. [4] The formulation according to any one of [1] to [3], having an osmotic pressure ratio to physiological saline of 0.3 to 3. [5] A preparation according to any one of [1] to [4], comprising a solvent composed of at least water and having a proportion of components other than rocuronium and the solvent of 15% by mass or less. [6] having a pH of 2.5 to 3.5, containing an acid, having an osmotic pressure ratio to physiological saline of 0.6 to 1.4, containing a solvent containing water at a proportion of 70% by mass or more, A preparation according to any one of [1] to [5], having a proportion of components other than rocuronium and the solvent of 15% by mass or less. [7] A preparation according to any one of [1] to [6], which has been sterilized. [8] A preparation according to any one of [1] to [7], enclosed in a container selected from vials, ampoules, syringes, and bags. [9] A method for storing a preparation according to any one of [1] to [8] at 10°C or higher or at room temperature (non-refrigerated).

[10] A rocuronium preparation that does not include a preparation containing rocuronium (rocuronium bromide) and hydrochloric acid [for example, (A) a preparation containing rocuronium and hydrochloric acid (hydrogen chloride) with a pH of 3.0, (B) a preparation containing rocuronium and hydrochloric acid with a hydrochloric acid concentration of 0.015 M, (C) a preparation containing rocuronium, hydrochloric acid, and sodium chloride with a pH of 3.0, (D) a preparation containing rocuronium, hydrochloric acid, and sodium chloride with a hydrochloric acid concentration of 0.015 M, (E) a preparation containing rocuronium, hydrochloric acid, and sodium chloride with a pH of 3.0 and a sodium chloride ratio of 0.9 w / v%, (F) a preparation containing rocuronium, hydrochloric acid, and sodium chloride with a hydrochloric acid concentration of 0.015 M and a sodium chloride ratio of 0.9 w / v%, (G) a preparation containing rocuronium, hydrochloric acid, and sodium chloride with a pH of 3.0, a hydrochloric acid concentration of 0.015 M, and a sodium chloride ratio of 0.9 w / v%, or (H) a preparation containing water with a rocuronium ratio of 1 w / v%, such as any of the preparations (A) to (G)] and a preparation obtained by heat-treating this preparation [for example, any of the preparations (A) to (H)] at 121°C for 20 minutes (for example, a preparation with a pH of 3.3, a preparation with a pH fluctuation of 0.3 or more before and after heat treatment, etc.), the preparation or method according to any of [1] to [9].

Advantages of the Invention

[0020] In the present invention, a novel rocuronium preparation can be provided. Such a preparation is usually stable despite not containing a buffer. For example, such a rocuronium preparation hardly decomposes and is stable even when stored for a long time without refrigeration or when subjected to treatment under conditions where high temperature and high pressure act. Therefore, the preparation of the present invention can be stored at room temperature and has excellent practicality.

[0021] In addition, due to the fact that the preparation of the present invention does not contain a buffer, the pH may relatively easily change. In particular, such a tendency is remarkable when subjected to high-temperature treatment for the purpose of sterilization or the like. However, according to the present invention, extremely unexpectedly, even when such a pH change occurs, sufficient stability of rocuronium can be ensured. In particular, the degree of its stability is sufficient, being comparable to or higher than that in the case of containing a buffer.

[0022] Furthermore, the present invention can provide a safe rocuronium preparation. For example, as described above, in the preparation of the present invention, excellent stability can be obtained without using a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof, which may be a factor for kidney disorders or the like.

[0023] Also, although it is considered that the buffer has little effect on physiological effects, in the present invention, since it can be made to not contain a buffer, the toxic effects of the buffer can be avoided, and safety can be more reliably ensured.

[0024] For example, in WO2015 / 001995 pamphlet, in a rocuronium preparation that requires a buffer in the same manner as the above-mentioned patent documents and the like, it is reported that vascular pain can be suppressed by setting the titratable acidity to 100 mEq or less. However, in the present invention, by not containing a buffer, it is easy to obtain a preparation with a very small titratable acidity, and thus a preparation with highly suppressed vascular pain (pain during injection).

Embodiments for Carrying Out the Invention

[0025] The preparation of the present invention contains rocuronium and has a pH within a predetermined range. Rocuronium has the following formula

[0026]

Chemical formula

[0027] The proportion of rocuronium in the preparation is not particularly limited and is appropriately selected according to the disease state, dosage form, etc. For example, it may be about 0.1 w / v% or more (for example, 0.1 to 10 w / v%), preferably about 0.3 w / v% or more (for example, 0.5 to 5 w / v%), and more preferably about 0.7 w / v% or more (for example, 0.8 to 3 w / v%). In the preparation of the present invention, even if rocuronium is contained at a relatively high concentration, rocuronium can be efficiently stabilized.

[0028] The preparation of the present invention does not contain a buffering agent (buffer solution).

[0029] Such a buffering agent (buffer solution) is not particularly limited as long as it can exhibit a buffering action. For example, carboxylic acid-based buffer solutions [for example, formic acid buffer solution, acetic acid buffer solution, citric acid buffer solution (for example, citric acid - sodium hydroxide buffer solution, etc.), tartaric acid buffer solution (for example, tartaric acid - sodium hydroxide buffer solution, etc.), phthalic acid buffer solution (for example, potassium hydrogen phthalate - hydrochloric acid buffer solution, etc.), etc.], phosphate-based buffer solutions [for example, phosphate buffer solution, citric acid - phosphate buffer solution, etc.], amino acid-based buffer solutions [for example, glycine buffer solution (for example, glycine - hydrochloric acid buffer solution, etc.), etc.] and the like can be mentioned. These buffering agents may be used alone or in combination of two or more.

[0030] The pH of the preparation of the present invention can be selected from a range of, for example, about 4 or less (for example, 1.5 to 3.8), 3.5 or less (for example, 1.8 to 3.5), preferably 3.4 or less (for example, 2 to 3.35), and more preferably 3.3 or less (for example, 2.2 to 3.3). In particular, the pH of the rocuronium preparation may be, for example, 2 to 3.5, preferably 2.5 to 3.5 (for example, 2.8 to 3.2), and may also be less than 3.5 (for example, 2 to 3.4), 3 or less [for example, less than 3 (for example, 2.2 to 2.8), etc.].

[0031] In a preparation containing no buffer as in the present invention, if the pH is too high or too low, the stability of rocuronium tends to decrease. Therefore, in the present invention, it is preferable to adjust the pH to a specific range that is not too high and not too low as described above.

[0032] The pH may be a value at a temperature of 20 to 30 °C.

[0033] The preparation of the present invention may contain a pH adjuster. The pH adjuster may be either an acid or a base (for example, an inorganic base such as sodium hydroxide), but usually, the pH adjuster may contain at least an acid.

[0034] Examples of such acids include inorganic acids {for example, hydrogen halides [for example, hydrogen chloride (or hydrochloric acid), phosphoric acid, boric acid, nitric acid, sulfuric acid, etc.]}, organic acids {for example, monocarboxylic acids [for example, alkanoic acids (for example, formic acid, acetic acid, etc.), hydroxyalkanoic acids (for example, glycolic acid, lactic acid, gluconic acid, etc.), etc.]}, polycarboxylic acids [for example, alkane polycarboxylic acids (for example, oxalic acid, succinic acid, adipic acid, etc.), hydroxyalkane polycarboxylic acids (for example, tartaric acid, malic acid, citric acid, etc.), alkene polycarboxylic acids (for example, maleic acid, fumaric acid, etc.), arene polycarboxylic acids (for example, phthalic acid, etc.), etc.] such as carboxylic acids; alkanesulfonic acids (for example, methanesulfonic acid, etc.), arenesulfonic acids (for example, benzenesulfonic acid, etc.) such as sulfonic acids, etc.

[0035] The pH adjuster (for example, an acid) may be a hydrate, an anhydride, etc., and for those having isomers (such as optical isomers, enantiomers, etc.), any isomer may be used.

[0036] Depending on the type of pH adjuster (acid), the stability of rocuronium in the preparation may vary slightly, but with an acid as described above, rocuronium can be efficiently stabilized.

[0037] The pH adjuster (especially an acid) may be used alone or in combination of two or more.

[0038] The concentration of the pH adjuster (for example, an acid) in the preparation may be selected from a range such as 1000 mM or less (for example, 1 - 800 mM, 3 - 500 mM, 5 - 250 mM), depending on its type, the desired pH, etc. In particular, it may be a relatively low concentration, for example, 200 mM or less (for example, 1 - 150 mM), more preferably 100 mM or less (for example, 5 - 90 mM).

[0039] In particular, when hydrogen chloride (hydrochloric acid) is used as the pH adjuster, the concentration in the preparation may be 50 mM or less, 40 mM or less, 30 mM or less, etc.

[0040] The preparation of the present invention may contain an isotonic agent. The isotonic agent is not particularly limited, and examples include saccharides (for example, glucose, fructose, lactose, etc.), sugar alcohols (for example, D - sorbitol, D - mannitol, xylitol, trehalose, glycerin, etc.), inorganic salts (for example, alkali metal or alkaline earth metal halides such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium bromide, magnesium bromide, etc.), polyethylene glycol (for example, macrogol 4000, etc.), glycols (for example, alkanediols such as propylene glycol, etc.), alcohols (for example, benzyl alcohol, etc.), taurine, nicotinic acid amide, etc.

[0041] The isotonic agent may be used alone or in combination of two or more.

[0042] When using an isotonic agent, the proportion of the isotonic agent is not particularly limited and is appropriately selected according to the desired osmotic pressure, the type of isotonic agent, etc. For example, it may be about 0.1 to 30 w / v%, preferably 0.2 to 20 w / v%, more preferably about 0.3 to 15 w / v%.

[0043] In addition, the preparation of the present invention may contain the specific components described in the above Patent Document 1, that is, a sulfoalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof, but usually may not contain them. In the present invention, since it is not necessary to contain such components, a rocuronium preparation can be stabilized with high safety without the risk of kidney disorders or the like.

[0044] Further, the preparation of the present invention may be colored or may be non-colored (not colored). Specifically, the preparation of the present invention may contain a dye (for example, fluorescein, etc.), but usually may not contain it.

[0045] In addition, the preparation of the present invention may be clear, and particularly may be colorless and clear.

[0046] The preparation of the present invention usually may contain a solvent (a solvent).

[0047] The solvent is not particularly limited, and examples thereof include water (purified water, etc.), ethanol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. The solvent may be used alone or in combination of two or more.

[0048] In particular, the solvent may be composed of at least water or may be composed of only water. In such a solvent containing water, the proportion of water may be, for example, 50% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, 95% by mass or more, 97% by mass or more, 100% by mass (only water), etc.

[0049] In the present invention, even when a formulation is constituted with a solvent containing water at such a high concentration, rocuronium can be efficiently stabilized.

[0050] In the rocuronium formulation of the present invention, if necessary, other components [for example, rocuronium, buffer, pH adjuster, isotonic agent (further sulfonylalkyl ether-β-cyclodextrin derivative or a pharmaceutically acceptable salt thereof, dye), components other than the solvent] may be blended.

[0051] The other components (additives) are not particularly limited, and examples thereof include solubilizing agents, suspending agents, soothing agents, preservatives, antioxidants, stabilizers, and anti-oxidants. The other components may be commercially available products, and may be used alone or in combination of two or more depending on the intended dosage form and the like.

[0052] As described above, the formulation of the present invention does not contain a buffer, but from the viewpoint of more reliably ensuring safety, even when other components are blended, the amount may be relatively small.

[0053] For example, when the formulation of the present invention contains other components, the proportion of the other components may be, for example, 10% by mass or less (for example, 0.001 to 8% by mass), preferably 5% by mass or less (for example, 0.005 to 3% by mass), and more preferably 2% by mass or less (for example, 1% by mass or less, 0.01 to 0.5% by mass, 0.1% by mass or less, etc.).

[0054] Also, in the formulation of the present invention (for example, a formulation containing a solvent), the proportion of the components other than rocuronium and the solvent (for example, pH adjuster, isotonic agent, and further other components if necessary) may be, for example, 15% by mass or less (for example, 0.3 to 10% by mass), preferably 10% by mass or less (for example, 0.5 to 8% by mass), and more preferably 7.5% by mass or less (for example, 0.7 to 7% by mass).

[0055] Furthermore, in the formulation of the present invention (for example, a formulation containing a solvent), the proportion of the components other than the solvent (total solid content) may be, for example, 25% by mass or less (for example, 0.5 to 22.5% by mass), preferably 20% by mass or less (for example, 0.8 to 17.5% by mass), more preferably 15% by mass or less (for example, 1 to 12.5% by mass).

[0056] The osmotic pressure of the formulation of the present invention is not particularly limited, but may be, for example, an osmotic pressure ratio to physiological saline of 0.1 to 10 (for example, 0.2 to 5), preferably 0.3 to 3 (for example, 0.5 to 2), more preferably 0.6 to 1.4 (for example, 0.7 to 1.3, 0.8 to 1.2, 0.9 to 1.1, about 1).

[0057] Note that the osmotic pressure ratio may be a value at a temperature of 20 to 30°C.

[0058] In the formulation of the present invention, even with such an osmotic pressure, sufficient stability of rocuronium can be ensured.

[0059] The rocuronium formulation of the present invention may be enclosed (sealed) in a container. In other words, the present invention also includes a container (a container containing inside) containing the rocuronium formulation.

[0060] In such a container, the above-mentioned formulation may usually be enclosed or sealed. The container can be appropriately selected according to the administration mode and the like, and examples include vials (vial bottles), ampoules, syringes (for example, prefilled syringes, etc.), bags, and the like.

[0061] The material of the container is not particularly limited, and examples include glass, metal, resin or plastic, etc. The container may be formed by combining these materials.

[0062] Note that the container (for example, at least the part of the container that comes into contact with the formulation) may be appropriately surface-treated (for example, blast treatment, coating treatment with a surface treatment agent, etc.).

[0063] Typical containers include containers made of glass (such as glass vials, glass ampoules, etc.).

[0064] The rocuronium preparation of the present invention can efficiently ensure stability even when enclosed (stored) in such a container.

[0065] The preparation of the present invention (for example, the preparation enclosed or stored in a container) may be subjected to various treatments such as sterilization treatment. Examples of the sterilization treatment include filtration sterilization treatment, high-temperature sterilization treatment, etc., and these treatments may be combined.

[0066] In particular, from the viewpoint of stability and the like, the preparation of the present invention may be subjected to sterilization treatment (such as filtration sterilization treatment, high-temperature sterilization treatment, etc.).

[0067] When performing high-temperature sterilization treatment, in the high-temperature sterilization treatment (high-temperature treatment), the treatment temperature may be, for example, 60°C or higher (for example, 70 to 200°C), 80°C or higher (for example, 90 to 180°C), 100°C or higher (for example, 105 to 160°C), 110°C or higher (for example, 115 to 150°C), 120°C or higher (for example, 120 to 140°C), etc.

[0068] The high-temperature treatment time may be, for example, 1 minute or longer (for example, 3 minutes or longer), 5 minutes or longer (for example, 7 minutes or longer), 10 minutes or longer, 15 minutes or longer, 20 minutes or longer, etc. The upper limit value of the high-temperature treatment time is not particularly limited, but may be 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 30 minutes, etc.

[0069] The preparation of the present invention (the container in which the preparation is enclosed or stored) can efficiently ensure stability even after undergoing such a high-temperature treatment.

[0070] The dosage form of the rocuronium preparation of the present invention is not particularly limited, but is usually a liquid preparation, and examples include parenteral preparations such as injections (intravenous injection, arterial injection, intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection, intraspinal injection, epidural injection), eye drops, nasal preparations, etc.

[0071] The rocuronium preparation of the present invention may be produced, for example, through at least a step of mixing at least each component [for example, rocuronium, solvent, pH adjuster, isotonic agent (and further other components) as required].

[0072] Various treatments can be appropriately performed on the preparation according to the content of the treatment and the like. For example, sterilization treatment and high-temperature treatment may be performed on the preparation prepared by mixing each component.

[0073] When enclosing in a container, the previously prepared preparation (the preparation obtained by mixing each component) may be enclosed in the container, or the preparation may be prepared in the container. High-temperature treatment is usually performed after enclosing the preparation in the container.

[0074] As described above, the rocuronium preparation of the present invention has high stability. For example, when the rocuronium preparation is stored at 60°C for 30 days, the production rate of the related substance C of rocuronium is 5% or less (for example, 0 to 4.8%), preferably 4.5% or less (for example, 0.1 to 4.2%), more preferably about 4% or less (for example, 0.5 to 3.8%), and it is also possible to make the production rate of the related substance C 3.5% or less (for example, 3.2% or less, 3% or less, 2.8% or less, 2.5% or less, 2.2% or less, 2% or less, 1.8% or less, 1.5% or less, etc.).

[0075] The related substance C is a main decomposition product of rocuronium and is also a substance described in the United States Pharmacopeia (USP) and the European Pharmacopeia (EP).

[0076] As described above, the rocuronium preparation of the present invention does not contain a buffer, so the pH may relatively easily fluctuate.

[0077] For example, when a rocuronium preparation is stored at 60°C for 30 days, the absolute value of the difference between the pH after storage and the pH before storage (or at the time of preparation of the preparation) (pH after storage - pH before storage) may be, for example, 0.01 or more, 0.03 or more, 0.02 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, etc., depending on the pH of the preparation. The upper limit value of the absolute value may be, for example, 1, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, etc.

[0078] Note that the condition of 60°C for 30 days may correspond to, for example, the condition when stored at room temperature (ordinary temperature, for example, about 25°C) for 36 months.

[0079] However, in the preparation of the present invention, unexpectedly, even in a case where such pH fluctuations are likely to occur, as described above, excellent stability can be ensured (for example, the production of related substance C can be suppressed to the same level as or higher than the case of containing a buffer).

[0080] Note that the production rate of related substance C and the fluctuation of pH as described above may be for the rocuronium preparation enclosed in a container (such as a glass vial or a glass ampule), or may be for the rocuronium preparation that has undergone high-temperature treatment.

[0081] As described above, the rocuronium preparation of the present invention is excellent in stability (thermal stability), and thus, in particular, it may be a preparation that can be stored at room temperature (or ordinary temperature or non-refrigerated temperature, for example, at 10 to 45°C, 12 to 40°C, 15 to 35°C, 20 to 30°C, etc.).

[0082] The present invention also includes a method for storing the rocuronium preparation. In such a storage method, the storage temperature may be a low temperature [for example, a temperature less than 10°C (for example, 2 to 8°C, etc.)], or may be 10°C or higher (for example, 10 to 45°C, 12 to 40°C, 15 to 35°C, 20 to 30°C) or room temperature (or ordinary temperature or non-refrigerated temperature).

[0083] The storage period is not particularly limited, and for example, it may be 10 days or more, 30 days or more, 2 months or more, 3 months or more, 6 months or more, 8 months or more, 10 months or more, 12 months (1 year) or more, 14 months or more, 16 months or more, 18 months or more, 20 months or more, 22 months or more, 24 months (2 years) or more, etc.

[0084] The upper limit value of the storage period is not particularly limited, and for example, it may be 10 years, 8 years, 6 years, 5 years, 4 years, 3 years, 2 years, 1.5 years (18 months), 1 year (12 months), etc.

[0085] During such storage, the pH of the rocuronium preparation can vary as described above. For example, during storage, the pH may be 0.01 or more, 0.03 or more, 0.02 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, etc. The upper limit value of the pH variation is, for example, 1, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, etc. As described above, in the present invention, even if such a pH variation occurs, the stability of rocuronium in the preparation is high.

[0086] The administration route of the rocuronium preparation of the present invention is not particularly limited. However, in the case of parenteral administration using an injection, intravenous, intra - arterial, subcutaneous, intradermal, intramuscular, intraperitoneal administration, etc. are preferred, and it is preferably appropriately selected according to the age, medical condition, and other conditions of the patient.

[0087] The dosage (usage amount) of the rocuronium preparation of the present invention varies depending on the patient's age, gender, weight, degree of disease, etc., and is not particularly limited. Generally, for adults, the total amount of the active ingredient (i.e., rocuronium) is usually about 0.01 to 100 mg per day, preferably about 10 to 60 mg. Also, the dosage regimen varies depending on the patient's age, gender, weight, degree of disease, etc., and is not particularly limited. Generally, it is appropriate to administer it once or several times (e.g., 2 to 4 times) a day. For example, intravenous administration is performed so that the dose of rocuronium is 0.6 mg / kg, and additional administration of 0.1 to 0.2 mg / kg by continuous infusion is performed as necessary during the operation.

[0088] The rocuronium preparation of the present invention is not particularly limited, but is preferably used under anesthesia. The anesthesia is not particularly limited, and for example, inhalation anesthetics and intravenous anesthetics are preferably mentioned. The inhalation anesthetics are not particularly limited, and for example, volatile inhalation anesthetics such as halothane, isoflurane, enflurane, methoxyflurane, sevoflurane, desflurane; gaseous inhalation anesthetics such as ethylene, cyclopropane, diethyl ether, chloroform, nitrous oxide or xenon can be mentioned. The intravenous anesthetics are not particularly limited, and for example, propofol, midazolam, ketamine, thiletamine, thiopental, methohexital or etomidate can be mentioned, and propofol, midazolam, etc. are preferable. These may be used alone or in combination of two or more. Commercially available products can also be used.

[0089] In addition, the present invention includes aspects in which the above configurations are variously combined within the technical scope of the present invention as long as the effects of the present invention are achieved.

Examples

[0090] Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by these examples, and many modifications are possible by those having ordinary knowledge in the art within the technical idea of the present invention.

[0091] In the examples, various properties were measured or evaluated as follows.

[0092] [pH] Measured at 20 - 30°C according to the Japanese Pharmacopoeia pH measurement method.

[0093] [Osmotic pressure ratio] According to the Japanese Pharmacopoeia osmotic pressure measurement method, the osmolality was measured, and the osmotic pressure ratio was calculated by dividing by the osmolality of physiological saline, which is 286 mOsm.

[0094] [Production rate of related substance (imp) C] Measured according to the USP HPLC test method.

[0095] (Example 1) To water for injection, rocuronium (rocuronium bromide), 1M hydrochloric acid, and sodium chloride were added to obtain a solution (formulation) with a pH of 3.0. The solution was passed through a filter with a pore size of 0.2 μm and sterilized by filtration.

[0096] In the solution, the rocuronium concentration was 10 mg / mL, the hydrogen chloride concentration was 16.8 mM, the sodium chloride concentration was 9 mg / mL, the total concentration of the components was 1.96% by mass, and the concentrations of hydrogen chloride and sodium chloride were 0.96% by mass.

[0097] Also, the osmotic pressure ratio of the solution to physiological saline was approximately 1.

[0098] The obtained solution (formulation) was filled into glass vials, heat-treated (treated with high-pressure steam at 121°C for 20 minutes), then stored at 60°C, and the pH and the production rate of related substance C were measured over time.

[0099] (Example 2) In Example 1, except that no heat treatment was performed, the pH and the production rate of related substance C were measured over time in the same manner as in Example 1.

[0100] (Reference Example 1) In Example 1, the pH and the production rate of related substance C were measured over time in the same manner as in Example 1, except that the solution obtained as described below was used.

[0101] To water for injection, rocuronium (rocuronium bromide), glycine, 1M hydrochloric acid, and sodium chloride were added to obtain a solution (formulation) with a pH of 3.0.

[0102] In the solution, the rocuronium concentration was 10 mg / mL, the glycine concentration was 73 mM, the hydrogen chloride concentration was 30 mM, and the sodium chloride concentration was 5 mg / mL. The concentration of the whole components was 2.16% by mass, and the concentrations of glycine, hydrogen chloride, and sodium chloride were 1.16% by mass.

[0103] Also, the osmotic pressure ratio of the solution to physiological saline was about 1.

[0104] (Reference Example 2) In Example 1, the pH and the production rate of related substance C were measured over time in the same manner as in Example 1, except that the solution obtained in Reference Example 1 was used and no high-temperature treatment was performed.

[0105] The formulation and results of the solution are shown in the following table.

[0106]

Table 1

[0107] (Examples 3 - 4, Reference Examples 3 - 4) In Examples 1 - 2 and Reference Examples 3 - 4, the pH and the production rate of related substance C were measured over time in the same manner, except that the container was changed to a glass ampoule.

[0108] The formulation and results of the solution are shown in the following table.

[0109]

Table 2

[0110] (Examples 5 to 8) In Example 1, except that the following solutions were used, the pH and the production rate of related substance C were measured over time in the same manner as in Example 1.

[0111] In Example 1, 1M hydrochloric acid was changed to 0.1M hydrochloric acid, and solutions with pH 2.0, 2.5, 3.5, and 4.0 were prepared, respectively.

[0112] (Reference Example 5) In Example 1, except that the following solution was used, the pH and the production rate of related substance C were measured over time in the same manner as in Example 1.

[0113] To water for injection, rocuronium (rocuronium bromide), acetic acid, sodium acetate, and sodium chloride were added to obtain a solution (formulation) with pH 4.0. This solution corresponds to the commercially available Esrac.

[0114] In the solution, the rocuronium concentration was 10 mg / mL, the acetic acid concentration was 134 mM, the sodium acetate concentration was 16 mM, and the sodium chloride concentration was 2.7 mg / mL. The concentration of the whole components was 2.3% by mass, and the concentration of the components other than rocuronium was 1.3% by mass.

[0115] Also, the osmotic pressure ratio of the solution to physiological saline was about 1.

[0116] The formulation and results of the solution are shown in the following table. In the following table, Example 1 and Reference Example 1 are also shown together.

[0117]

Table 3

[0118] (Examples 9 to 12, Reference Example 6) In Example 2, except that the solutions obtained in Examples 5 to 8 and Reference Example 5 were used, respectively, the pH and the production rate of related substance C were measured over time in the same manner as in Example 2.

[0119] The solution formulation and the results are shown in the following table, which also shows Example 2 and Reference Example 2.

[0120] [Table 4]

[0121] (Examples 13 to 17) The pH and the production rate of related substance C were measured over time in the same manner as in Example 1, except that the following solutions were used.

[0122] In Example 1, phosphoric acid, methanesulfonic acid, tartaric acid, lactic acid, or citric acid was used instead of 1 M hydrochloric acid to prepare a solution of pH 3.0.

[0123] The solution formulations and results are shown in the following table, which also shows Example 1, Reference Example 1, and Reference Example 5.

[0124] [Table 5]

[0125] (Examples 18 to 22) The pH and the production rate of related substance C were measured over time in the same manner as in Example 2, except that the following solutions were used.

[0126] In Example 2, phosphoric acid, methanesulfonic acid, tartaric acid, lactic acid, or citric acid was used instead of 1 M hydrochloric acid to prepare a solution of pH 3.0.

[0127] The solution formulations and results are shown in the following table, which also shows Example 2, Reference Example 2, and Reference Example 6.

[0128] [Table 6] [Industrial Applicability]

[0129] The present invention can provide a rocuronium preparation useful as a muscle relaxant or the like.

Claims

1. A rocuronium formulation that contains rocuronium, has a pH of less than 3.8, and does not contain a buffer (however, excluding a 100 mL formulation that contains 0.90 g of sodium chloride, 15 g of 0.1 M hydrochloric acid, 1.0 g of rocuronium bromide, and water for injection).

2. The formulation according to claim 1, having a pH of 3.5 or less.

3. The formulation according to claim 1 or 2, containing an acid.

4. The formulation according to any one of claims 1 to 3, having an osmotic pressure ratio to physiological saline of 0.3 to 3.

5. The formulation according to any one of claims 1 to 4, containing a solvent composed of at least water, wherein the proportion of components other than rocuronium and the solvent is 15% by mass or less.

6. having a pH of 2.5 to 3.5, containing an acid, having an osmotic pressure ratio to physiological saline of 0.6 to 1.4, containing a solvent that contains water at a proportion of 70% by mass or more, The formulation according to any one of claims 1 to 5, wherein the proportion of components other than rocuronium and the solvent is 15% by mass or less.

7. A formulation that contains rocuronium, has a pH of less than 3.3, and is sterilized, and does not contain a buffer.

8. The formulation according to any one of claims 1 to 7, enclosed in a container selected from vials, ampoules, syringes, and bags.

9. A method of storing the formulation according to any one of claims 1 to 8 at 10°C or higher or at room temperature.

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